Abstract / Description of output
Background
Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary
embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the
VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying
malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an
underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would
ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore,
an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to
improvements in cancer-related mortality and morbidity. This is the third update of the review first published in 2015.
Objectives
To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the
lower limb or PE) is effective in reducing cancer- or VTE-related mortality and morbidity and to determine which tests
for cancer are best at identifying treatable cancers early.
Search methods
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL,
MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry
Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify
additional studies.
Selection criteria
Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific
tests for identifying cancer or clinically indicated tests only were eligible for inclusion.
Cochrane Vascular Group, Robertson, Robertson, Broderick, Yeoh, and... https://archie.cochrane.org/sections/documents/view?version=z21093...
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Data collection and analysis
Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the
certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of
interest were all-cause mortality, cancer-related mortality and VTE-related mortality.
Main results
No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two
studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the
physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission
tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the
physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias
(early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing
alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was
downgraded further as detection bias was present in one study with a low number of events.
When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two
studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality
(odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low-certainty evidence).
One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested
participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively
tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control
group (OR 5.00, 95% CI 1.05 to 23.76; low-certainty evidence). There was no clear difference in detection of
advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively
tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; lowcertainty evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1
month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of
diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95%
CI 0.59 to 2.93; 396 participants; 2 studies; low-certainty evidence). Neither study measured all-cause mortality, VTErelated morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant
satisfaction or quality of life.
When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus
PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to
3.04; 1248 participants; 2 studies; moderate-certainty evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to
1.52; 1248 participants; 2 studies; moderate-certainty evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to
2.17; 854 participants; 1 study; moderate-certainty evidence). Regarding stage of cancer, there was no clear
difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; low-certainty evidence) or
advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low-certainty evidence) stages of cancer. There
was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248
participants; 2 studies; moderate-certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testing
group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related
mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.
Authors' conclusions
Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage
of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the
effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in
reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no
benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be
made.
Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary
embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the
VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying
malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an
underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would
ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore,
an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to
improvements in cancer-related mortality and morbidity. This is the third update of the review first published in 2015.
Objectives
To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the
lower limb or PE) is effective in reducing cancer- or VTE-related mortality and morbidity and to determine which tests
for cancer are best at identifying treatable cancers early.
Search methods
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL,
MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry
Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify
additional studies.
Selection criteria
Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific
tests for identifying cancer or clinically indicated tests only were eligible for inclusion.
Cochrane Vascular Group, Robertson, Robertson, Broderick, Yeoh, and... https://archie.cochrane.org/sections/documents/view?version=z21093...
1 of 37 01/10/2021, 09:18
Data collection and analysis
Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the
certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of
interest were all-cause mortality, cancer-related mortality and VTE-related mortality.
Main results
No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two
studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the
physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission
tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the
physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias
(early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing
alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was
downgraded further as detection bias was present in one study with a low number of events.
When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two
studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality
(odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low-certainty evidence).
One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested
participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively
tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control
group (OR 5.00, 95% CI 1.05 to 23.76; low-certainty evidence). There was no clear difference in detection of
advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively
tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; lowcertainty evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1
month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of
diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95%
CI 0.59 to 2.93; 396 participants; 2 studies; low-certainty evidence). Neither study measured all-cause mortality, VTErelated morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant
satisfaction or quality of life.
When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus
PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to
3.04; 1248 participants; 2 studies; moderate-certainty evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to
1.52; 1248 participants; 2 studies; moderate-certainty evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to
2.17; 854 participants; 1 study; moderate-certainty evidence). Regarding stage of cancer, there was no clear
difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; low-certainty evidence) or
advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low-certainty evidence) stages of cancer. There
was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248
participants; 2 studies; moderate-certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testing
group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related
mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.
Authors' conclusions
Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage
of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the
effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in
reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no
benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be
made.
| Original language | English |
|---|---|
| Journal | Cochrane Database of Systematic Reviews |
| DOIs | |
| Publication status | Published - 4 Oct 2021 |